(5S, 10S)-10-benzyl-16-methyl-11,14,18-trioxo-15,17,19-trioxa-2,7,8-trithia-12-azahenicosan-5-aminium (E)-3-carboxyacrylate salt, referred herein as “Compound (I)” of following formula:
is a pro-drug of the asymmetric disulfide which is composed of the selective neutral aminopeptidase (APN) inhibitor, ((S)-1-mercapto-4-(methylthio)butan-2-aminium), and of the selective neprilysin (NEP) inhibitor, ((S)-2-(2-benzyl-3-mercaptopropanamido)acetic acid). Compound (I) has been proven to be an efficient painkiller, as described by Poras et al. in J Med Chem, 2014, 57, 5748-5763.
Compound (I) and its use as painkiller were first disclosed in patent application WO2007/048787. The process exemplified in WO 2007/048787 allows the preparation of compound (I), in 4 steps from 3-(acetylthio)-2-benzylpropanoic acid (A), (S)-tert-butyl 1-mercapto-4-(methylthio)butan-2-ylcarbamate (B) and 2-(1-(ethoxycarbonyloxy)ethoxy)-2-oxoethanaminium chloride (C). Technical synthetic specifications, particularly enzymatic resolution, numbers of equivalents, solvents and/or purification techniques involved in this process, do not allow it to be efficiently and easily converted into an industrial scale.
A permanent aim in organic synthesis is to create synthesis processes that can be transposed into industrial conditions. In order to meet requirements for industrial processes, different parameters of the synthesis are to be optimized. Firstly, solvents must be as little volatile as possible, in order to be easily recoverable.
The temperatures involved preferably remain in an easily accessible range, and easy to proceed purification should be privileged. Finally, reactions mixtures and isolated products are preferably thermally stable.
Current Good Manufacturing Practice (c-GMP) has been defined for preparation of drug products for administration to humans or animals. GMP regulations require a quality approach to manufacturing, enabling companies to minimize or eliminate instances of contamination, mix-ups, and errors. To the applicant knowledge, no industrially applicable process to synthesize the compound (I) has been described so far. Therefore, a need remains for a process for preparing compound (I) that can be adapted easily and efficiently to industrial scale, in particular a process wherein toxic solvents such as chlorinated solvents, enzyme resolution, and column chromatography are not used.